Acetylcholine is an ester of choline and acetic acid, the prototype for a small family of choline ester compounds. The choline moiety of ACh contains a quaternary ammonium group that gives ACh a permanent positive charge, making it very hydrophilic and membrane impermeant.

ACh is degraded by a group of enzymes called cholinesterases. These enzymes catalyze the hydrolysis of ACh to choline and acetic acid (Fig. 12.1). The active center of cholinesterase has two areas that interact with ACh: the anionic site and the esteratic site. The anionic site contains a negatively charged amino acid that binds the positively charged quaternary ammonium group of ACh through coulombic forces. This probably serves to bring the ester linkage of ACh close to the esteratic site of the enzyme. The esteratic site contains a serine residue, which is made more reactive by hydrogen bonding to a nearby histidine residue. The nucleophilic oxygen of the serine reacts with the carbonyl carbon of ACh, thereby breaking the ester linkage. During this reaction, choline is liberated and an acetylated enzyme is formed. The latter intermediate is rapidly hydrolyzed to release acetic acid and regenerate the active enzyme. The entire process takes about 150 microseconds, one of the fastest enzymatic reactions known.

There are two major types of cholinesterases: acetylcholinesterase (AChE) and pseudocholinesterase (pseudo-ChE). AChE (also known as true, specific, or erythrocyte cholinesterase) is found at a number of sites in the body, the most important being the cholinergic neuroeffector junction. Here it is localized to the pre-junctional and postjunctional membranes, where it rapidly terminates the action of synaptically released ACh. It is essential to recognize that the action of ACh is ter-

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